Malaria is the most important parasitic disease of man, with over 1 million deaths per year and more than 300 million cases annually. New drugs are urgently required to combat this deadly disease. Due to a limited number of chemotypes and documented resistance to the available drugs, there is renewed international effort aimed to discover and develop new leads with potential to prevent or treat malaria. Most antimalarial drug discovery focuses on the erythrocytic stages of malaria that cause disease, yet to eliminate malaria compounds are required to kill liver stages as well as the infective stages for mosquitoes. The only approved drug with these combined properties is primaquine, an 8-aminoquinoline (8AQ) that has weak erythrocytic stage activity and is toxic in glucose-6-phosphate dehydrogenase deficient individuals. Therefore, the most significant need for future malaria elimination efforts is a compound that is safe and effective at killing parasites at all stages of development in the patient. With the exception of 8AQs, very few compound series have demonstrated activity against the exo-erythrocytic (EE) stages in the liver as well as erythrocytic and gametocyte stages. Endochin and 4(1H)-quinolones are known to possess causal prophylactic activity (kill growing EE stage parasites) and potent erythrocytic stage inhibition in avian malaria models, but not against malaria parasites in mammals. Furthermore, a quinolone ester ICI56,780 has been shown to produce a radical cure in P. cynomologi infected rhesus monkeys (eradicate dormant EE parasites);however, rapid development of resistance hampered its further development. Many of these studies were conducted over 20 years ago without an adequate evaluation in current preclinical efficacy models or without assessing the compounds'physicochemical properties. The broad long term objectives of this proposal are to progress 3-alkyl and 3-(hetero)aryl-4(1H)- quinolones, tetrahydroacridones, and 7-(2-phenoxyethoxy)-4(1H)-quinolones as antimalarial agents and to determine their mechanism of action and potential for resistance by utilizing chemical and biochemical tools. The three chemotypes possess in vivo liver stage activity, in vivo blood stage activity, gametocytocidal activity, and/or activity in the mosquitoes. PUBLIC HEALTH RELEVANCE: Malaria continues its devastating impact on the health of human populations in tropical regions, with over 500 million cases and the death of 1 to 3 million individuals each year. The hardest hit region is sub-Saharan Africa, which accounts for an estimated 90% of all deaths, occurring primarily in children less than five years of age. The two most prevalent species causing human disease are Plasmodium falciparum and P. vivax, both of which are increasingly difficult to treat and control due to the emergence of drug resistance and lack of preventive drugs for the populations at highest risk, predominantly children and pregnant women. This proposal aims at developing new antimalarial compounds displaying activity against the blood stages of malaria, the liver stages, as well as the infective stages for mosquitoes. .